Image registration is a fundamentally important capability in modern neuroscience and clinical medicine. Normalization in functional imaging studies, studies of shape changes in growth, aging, and disease, overlaying surgical plans on intraoperative images, and geometric distortion correction are examples of important applications of image registration. There are dozens of needs for registration in both intrasubject and intersubject applications as well. Therefore, any improvement in image registration performance will have an immediate impact on the scientific and clinical communities. Despite numerous advances in image reconstruction algorithms, the use of multiple modalities (or tissue contrasts) to carry out image registration is a virtually untapped area. The vastly dominant framework is to register a single image of the subject to another single image of the target, and if multiple images are available of either subject or target, they are registered by using the transformation derived from the single image registration. The proposed research will develop, evaluate, and validate a very simply explained but quite radical idea for multi-modal registration. The basic idea is to synthesize a proxy image from the subject image that has the same tissue contrast and intensity range as the target image and then use a conventional metric such as sum-of-square difference to carry out the registration between the subject proxy and target. Preliminary results demonstrate significant benefits in this approach. In the grant we will: 1) Optimize proxy multimodal image registration by exploring its theoretical justification as well a key parameters of the overall approach; 2) Apply proxy multimodal image registration to three key applications in neuroscience in order to validate the method and develop principles of best practice; and 3) Write open source software to carry out image synthesis, similarity computation, and rigid and deformable registration using the proxy image concept. Both the software to synthesize images for use in a user's favorite image registration method as well as software to carry out the entire proxy registration process in an optimized way will be made publicly available as open source computer code. The results of this research will lead to a new era in image registration by changing the way researchers and practitioners acquire and use data for neuroscientific studies and clinical medicine.